Crystallization Kinetics in Fasted-State Simulated and Aspirated Human Intestinal Fluids

Abstract

To enhance the bioavailability of poorly soluble therapeutics, enabling formulations that generate supersaturation are currently of great interest. There is limited knowledge of how the gastrointestinal environment can influence the complex phase behavior of these systems, in particular, crystallization. Simulated media are generally used to mimic physiologically relevant fluids, although their predictability remains unknown for crystallizing systems since they are simplified models of the gastrointestinal fluids. The purpose of this study was to evaluate and compare how different simulated media, as well as aspirated intestinal fluid, impact the phase behavior of supersaturated solutions of two poorly soluble compounds, atazanavir and posaconazole, in fasted-state conditions. The onset of nucleation and progression of crystallization were found to be highly medium dependent. In the aspirated fluid, the crystallization kinetics for both compounds was significantly reduced compared to commercial simulated media. The use of simple buffers or current simulated fluids as surrogates for intestinal fluids appears to require further verification when attempting to predict crystallization kinetics of supersaturated solutions, based on the observed lack of correlation between commercial media and human fluids. The findings highlight the importance of carefully considering the composition of in vitro testing media for assessing crystallization kinetics, particularly in the context of supersaturating formulations.

Phase Behavior and Crystallization Kinetics of a Poorly Water-Soluble Weakly Basic Drug as a Function of Supersaturation and Media Composition

“…Previously, it has been speculated that the more rapid crystallization rate in biorelevant media might be due to a reduction in the interfacial free energy, resulting from surfactant adsorption at the crystal nucleus−water interface. 74,75 However, analysis of the induction time data by CNT does not show a trend in the induction time with the interfacial free energy, as summarized in Table 4. For example, values of γ are similar in phosphate buffer and FeSSIF V1, despite different induction times.…”

Professor Roger Davey: Master ofAllCrystal Trades

“…Effective nucleation inhibition correlated with effective growth inhibition. This correlation is examined further in the paper presented here on two larger drug molecules crystallizing from simulated intestinal fluids …”

“…This correlation is examined further in the paper presented here on two larger drug molecules crystallizing from simulated intestinal fluids. 18 Roger neither forgets nor forgives materials whose behavior cannot be explained to his satisfactionhe revisits them. One of many examples is α-resorcinol, which was revisited 31 years after his first investigation of its "dead zone".…”

“…More than 20 crystallization scientists trained by Roger have gone on to work in the pharmaceutical industry for at least six different companies. This virtual special issue in Celebration of the Career of Roger Davey contains papers that deal with pharmaceutical materials − or arise from the collaboration between academia and the pharmaceutical industry − or come directly from the pharmaceutical industry. , …”

Crystallinity: A Complex Critical Quality Attribute of Amorphous Solid Dispersions

“…Media composition also influences crystallization kinetics. Nucleation induction time can both increase or decrease in the presence of complex media when compared to its blank buffer . Varied levels of lecithin and bile salts have been shown to alter crystallization behavior. ,− The diversity of bile salts in vivo compared to the commercially available biorelevant media (sodium taurocholate only) is an additional complicating factor to media design for predictive in vitro dissolution testing. ,, Such variation in the in vitro test design could lead to consequences for formulation design decisions, for establishing accurate in vitro–in vivo correlations, or for assessing risk of crystallinity in the formulation.…”